Pancreatic and hepatocellular cancers have poor survival rates. Based on data from the prior funding cycle showing that the multi-kinase inhibitor sorafenib synergistically interacts with the histone deacetylase inhibitor (HDACI) vorinostat to activate CD95 and kill renal, hepatocellular and pancreatic cancer lines, Bayer and Merck have sponsored phase I trials that will start in 2009. We also have published data demonstrating that geldanamycins (17AAG, 17DMAG) + MEK1/2 inhibitors synergize to kill liver and pancreatic tumor cells via CD95 activation. Both drug combinations cause a novel form of CD95 activation which is obligate for cell killing, but whether these combinations utilize all of the same molecular mechanisms to activate CD95 is unknown. We hypothesize based on published and preliminary data that Ca2+-dependent ROS generation by combined HSP90 antagonist and MEK1/2 inhibitor exposure will represent a key signal for ceramide- dependent CD95 activation and cell killing. We hypothesize, based on published and preliminary data, that inhibition of the class III RTK, PDGFRb, will represent a key primary target for sorafenib in the regulation of CD95 toxicity and autophagy regulation. We hypothesize that HDACIs potentiate sorafenib toxicity, in part, because they increase as a secondary event expression of CD95 and/or FAS-L via NFkB activation. Thus: Specific Aim 1: To determine the molecular mechanisms by which geldanamycin + MEK1/2 inhibitor treatment activates CD95. Specific Aim 2: To determine the molecular mechanisms by which sorafenib and vorinostat treatment activates CD95. Specific Aim 3: To determine mechanistically the relative importance of promoting additional extrinsic or intrinsic pathway activation to enhance the lethality of sorafenib+vorinostat in vitro and in vivo. Our goal is to determine in precise molecular detail the mechanisms of action of these drug combinations upstream of CD95 to improve their future clinical application, and to progress our yet-to-be translated findings from the bench / vivarium, to the bedside.